Uric Acid-Induced Inflammation in Cerebral Malaria

Ana Rodriguez, Ph.D.

Funded in September, 2009: $200000 for 3 years

Determining how cerebral malaria develops and how to prevent it

Researchers will study how overwhelming brain inflammation develops in some patients with malaria and results in disabling and potentially deadly cerebral malaria.

More than 500 million people worldwide suffer from malaria infection, produced by the Plasmodium parasite that is transmitted by mosquito bite and enters the bloodstream. Some infected patients develop cerebral malaria and suffer severe damage to the brain; as many as one-third of them die. Scientists know that cerebral malaria is caused by excessive inflammation that promotes the adhesion of infected red blood cells to the layer of “endothelial” cells that line the inside of the narrow (blood vessel) capillaries in the brain. Still unknown, however, is what triggers this exaggerated inflammatory response. The investigators have observed that the infected red blood cells release uric acid, and they hypothesize that it contributes to the massive inflammation that triggers the onset of cerebral malaria. They further hypothesize that treatment aimed at inhibiting this uric acid-induced pathway can prevent cerebral malaria.

Collaborating with a leading patient-oriented malaria researcher in Malawi and a mouse model immunity expert, this established investigator will test her hypotheses in four steps in cells from malaria-infected patients and in the mouse model. They first will determine whether uric acid released by infected red blood cells promotes the release of inflammatory proteins (called “cytokines”) that induce endothelial cells lining the brain’s capillaries to form adhesive molecules to which the infected red blood cells then attach. Next they will explore how the cytokines are released: they anticipate that uric acid activates specific proteins in innate immune dendritic cells to cause them to release the cytokines. Third, they will quantify the amount of uric acid crystals in the brain in the mouse model and in autopsied brains of patients who died from cerebral malaria. If these steps confirm that this process results in massive brain inflammation, they then will explore a combination method to prevent inflammation in the mouse model: 1) drugs to inhibit uric acid and its induction of inflammation combined with 2) treatment to decrease oxidative stress, an important function usually performed by uric acid.

Significance: If cerebral malaria is produced by uric acid’s stimulation of massive immune inflammation in the brain, uric acid will become an important target for potential preventive strategies, including two tested in this study.

Uric Acid-Induced Inflammation in Cerebral Malaria

Infection with Plasmodium parasite results in 500 million cases and 1-2 million deaths from malaria annually. Cerebral malaria is a complication caused by excessive inflammatory conditions that damage endothelial cell integrity and facilitate adhesion of erythrocytes infected with Plasmodium falciparum to endothelial cells in brain capillaries. It has a fatality rate of 10 and 30%.

The causes of the excessive inflammatory response induced during malaria, and in particular during cerebral malaria, are not well characterized. Our previous results indicate that uric acid derived from Plasmodium-infected erythrocytes mediates the inflammatory response induced by malaria in mice and human immune cells.

We intend to determine the role of uric acid and its signaling pathway in the generation of cerebral malaria and test whether inhibition of this inflammatory pathway reduces the incidence of cerebral malaria. For this purpose we will use mice models and also samples from patients with cerebral malaria.

Since there are no drugs available specifically for the treatment of cerebral malaria, understanding the mechanisms that underlie this deadly condition is essential for the development of new therapeutic approaches.

Ana Rodriguez, Ph.D.

Dr. Ana Rodriguez obtained a Ph.D. from Universidad Autonoma de Madrid (Spain) and completed her training in immunology and parasitology at Yale University and at the Curie Institute in Paris. She became an independent researcher focused on malaria in 1999 at New York University School of Medicine. Since then, she has focused her research efforts in malaria, one of the major killer diseases in the world. The main goal of her laboratory is to study the inflammatory response induced by Plasmodium, the causative agent of malaria,that are responsible for the overwhelming inflammation that induces most of the pathology observed in this disease. This basic approach has provided the basis for translational research, which is currently being developed in her laboratory that intends to find effective therapies to inhibit malaria-induced inflammation and pathology.

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